PROJECT SUMMARY Emerging evidence indicates that platelets, which have a well-established role in the pathophysiology of thrombosis, have a complex and dynamic role in modulating inflammation. Our recent studies have associated platelets with both anti- and pro-inflammatory properties via platelet/leukocyte interactions. Based on the platelet paradigm in hemostasis and thrombosis, we provide evidence platelet/monocyte and platelet/neutrophil interactions represent a ?platelet-dependent switch? that alters leukocyte phenotype and function during the dysregulated inflammatory response associated with sepsis. The medical management of sepsis remains a worldwide problem, and sepsis ranks in the top 10 causes of death in the U.S. As sepsis progresses, the dynamic interplay between platelets, thrombosis, and inflammation presents major challenges to understanding the molecular pathophysiology of the disease. We have documented the platelet adhesion receptor glycoprotein (GP) Ib-IX is a modulator of serum cytokine levels, monocyte phenotype, and neutrophil phenotype during the progression of sepsis in animal models. We also correlate human GPVI platelet haplotypes with circulating pro-inflammatory platelet microparticle (pMPs) levels released following platelet activation. Based on these preliminary findings we propose the testable hypothesis: the interaction of neutrophils and monocytes with circulating non-activated platelets dampens inflammation; whereas interaction with activated platelets or pMPs enhances inflammation. To test this hypothesis, we propose Aim 1: to define the mechanism by which GPIb-IX dependent platelet-leukocyte interactions affect cell phenotype, activation state, and cytokine release; and Aim 2: to demonstrate that platelet activation, and more specifically the platelet GPVI-dependent release of pMPs, induces pro-inflammatory leukocyte phenotypes following the induction of a systemic inflammatory response. Completion of these studies will define the functional role and mechanisms by which platelets regulate inflammatory responses and will represent a significant advancement in understanding the pathophysiology of sepsis in patients. This new knowledge should drive innovative strategies for the diagnosis and clinical management of sepsis and long term provide clinicians with critical information for managing septic patients receiving anti-platelet therapy.